Proteins in Disease 1041 Increased risk of Alzheimer s disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid

pathology? G.J. Biessels1 and L.J. Kappelle2 Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands Abstract Type II diabetes mellitus (DM2) is associated with an increased risk of cognitive dysfunction

and dementia. The increased risk of dementia concerns both Alzheimer s disease and vascular dementia. Although some uncertainty remains into the exact pathogenesis, several mechanisms through which DM2 may affect the brain have now been identified. First, factors related to the metabolic syndrome , a cluster of metabolic and vascular risk factors (e.g. dyslipidaemia and hypertension) that is closely linked to DM2,

may be involved. A number of these risk factors are predictors of cerebrovascular disease, accelerated cognitive decline and dementia. Secondly, hyperglycaemia may be involved, through adverse effects of potentially toxic glucose metabolites on the brain and its vasculature. Thirdly, insulin itself may be involved. Insulin can directly modulate synaptic plasticity and learning and memory, and disturbances in insulin signalling pathways in

the periphery and in the brain have recently been implicated in Alzheimer s disease and brain aging. Insulin also regulates the metabolism of -amyloid and tau, the building blocks of amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of Alzheimer s disease. In this paper, the evidence for the association between DM2 and dementia and for each of these underlying mechanisms will

be reviewed, with emphasis on the role of insulin itself. DM (diabetes mellitus) is associated with slowly progressive end-organ damage in the brain [1] . Mild to moderate impairments of cognitive functioning has been reported both in patientswithDM1(TypeIDM)[2],andinpatientswithDM2 (Type II DM) [3,4] . Clinically relevant deficits, however, mainly occur in elderly patients with DM2 [5] , who may experienceproblemswithday-to-dayfunctioningduetotheir

cognitive impairments [6] . The potential impact of DM on cognition in the elderly is further emphasized by several large epidemiological surveys that report an increased incidence of dementia among DM patients, apparently concerning both Alzheimer s disease and vascular dementia [3,7 9] . The observation that the effects of DM on the brain are most pronounced in the elderly has been

attributed to an interaction between DM and the normal aging process of the brain [10,11] . Differences between the pathophysiology of DM1 and DM2 are also likely to play a role [11] , as the latter is by far the most common form among the elderly. In DM1, the principal defect is an autoimmune-mediated destruction of pancreatic -cells, leading to insulin

deficiency, whereas in DM2 the principal defect is insulin resistance, leading to Key words: Alzheimer s disease, brain aging, cognitive dysfunction, insulin-induced amyloid, metabolic syndrome, Type II diabetes mellitus. Abbreviations used: A, -amyloid; APOE, apolipoprotein E; DM, diabetes mellitus; DM1, Type I DM; DM2, Type II DM; IDE, insulin-degrading enzyme; LDL, low-density lipoprotein; MRI, magnetic resonance imaging. 1To whom correspondence should

be addressed, at Department of Neurology, G03.228, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands (email g.j.biessels@neuro.azu.nl) . 2On behalf of the Utrecht Diabetic Encephalopathy Study Group (see Acknowledgements) a relative insulin deficiency. Moreover, DM2 occurs in the context of a cluster of metabolic and vascular risk factors, which is referred to as

the so-called metabolic syndrome [12] . The metabolic syndrome itself, with or without hyperglycaemia, is associated with atherosclerotic cardiovascular disease, ischaemic stroke and with cognitive decline and dementia [13] . A key question is therefore whether disturbances in insulin and glucose metabolism or other factors from the metabolic syndrome lead to impaired cognition in DM2. The present work aims to

provide an overview on the waysinwhichdisturbancesinglucoseandinsulinmetabolism and other factors related to the metabolic syndrome may be implicated in the accelerated cognitive decline and the increased risk of dementia in patients with DM2 (Figure 1) . Cognitive dysfunction and dementia in DM2: underlying mechanisms A role for hyperglycaemia? Several lines of evidence suggest that toxic effects of hyperglycaemia

are involved in the development of diabetic end-organdamagetothebrain[14].Hyperglycaemicrodents, for example, express cognitive impairments and functional and structural alterations in the brain [14] . Toxic effects of high glucose levels are mediated through an enhanced flux ofglucosethroughtheso-calledpolyolandhexosaminepathways, disturbances of intracellular second messenger pathways, an imbalance in the generation and scavenging C 2005 Biochemical Society

Biochemical Society Transactions (2005) Volume 33, part 5 Figure 1 Suggested pathogenesis of cognitive decline in DM2 Insulin resistance and risk factors related to the metabolic syndrome lead to DM2. The adverse effects of the metabolic syndrome and DM2 on the brain are mediated through ischaemic cerebrovascular disease, in concertwithotherfactorsfromthemetabolicsyndrome.Hyperglycaemia plays an additional role through toxic effects on brain

tissue and the development of cerebral microangiopathy. Alterations in insulin metabolism can also directly affect the brain, through involvement in synaptic plasticity and amyloid and tau metabolism. Ischaemic cerebrovasculardiseaseplaysamodulatingroleintheselatterprocesses. of reactive oxygen species, and by advanced glycation of important functional and structural proteins [15] . These processesdirectlyaffectbraintissueandleadtomicrovascular changes in the brain [11,14] . Still, hyperglycaemia is unlikely

to be the only factor in the development of cognitive impairments in DM2: previous studiesinDM2patientsdonotinvariablyshowanassociation betweenchronichyperglycaemia,asassessedbyHbA1levels, and the severity of cognitive impairments [3,10] . Moreover, changes in cognition may already develop in pre-diabetic stages , such as impaired glucose tolerance, or in newly diagnosed DM2 patients that have not yet been exposed to long-term hyperglycaemia [16,17] . A role

for the metabolic syndrome? DM2andinsulinresistancearecloselyassociatedwithfactors such as obesity, atherogenic dyslipidaemia [elevated triacylglycerol level, small LDL (low-density lipoprotein) particles, low HDL (high-density lipoprotein) cholesterol] , raised blood pressure, and pro-thrombotic and pro-inflammatory states. Together these factors constitute the metabolic syndrome, or insulin resistance syndrome [12,18] . A number of factors from this syndrome have been identified as independent predictors of cerebrovascular

disease, ischaemic stroke and accelerated cognitive decline and dementia (e.g. [13,16,19 21]) . The combined occurrence of these risk factors in the metabolic syndrome might reinforce these effects [19,22 24] . Given the clustering of insulin resistance, hypertension and dyslipidaemia in DM2 it may be difficult to determine which factor is the prime determinant in the development of cognitive dysfunction. The main

question, however, is to determine if the metabolic syndrome is indeed a strong predictor of cognitive dysfunction in DM2, and if thiseffectis(partially)independentofdisturbancesinglucose and insulin metabolism. Involvement of ischaemic cerebrovascular disease? DM2 and the metabolic syndrome are risk factors for atherosclerosis of the carotid and intracranial arteries [22,25] , thus increasing the risk of stroke, and of cognitive

decline and dementia [26] . In the long term, exposure to hyperglycaemia in DM may lead to abnormalities in cerebral capillaries, such as basement membrane thickening [27] . These microvascular changes may also lead to chronic and insidious ischaemia of the brain, thus contributing, for example, to the development of subcortical white-matter lesions. On a population level these lesions are associated

with cognitive impairments, particularly related to frontal lobe functions [28] . Although white-matter lesions are also common among healthy elderly subjects, their prevalence and severity is increased in patients with vascular risk factors or ischaemic vascular disease, and indementedpatients[28].MRI(magneticresonanceimaging) studies in DM2 patients indeed show an increased severity of white-matter lesions {[29] , and S.M. Manschot et al. , Utrecht

Diabetic Encephalopathy Study Group (see Acknowledgements) , unpublished work} , and an increased incidence of (silent) brain infarcts [30] . An interaction with aging? As the effects of DM on the brain are most pronounced in the elderly, one may suggest that the aging brain is more susceptible to the effects of DM or that the effects of

DM and aging interact. In fact, several of the mechanisms that are assumed to mediate the toxic effects of hyperglycaemia on the brain, such as oxidative stress, the accumulation of advanced glycation end-products and microangiopathy, are also involved in brain aging [11] . Moreover, experimental studies indicate that the behavioural and neurophysiological consequences of DM are accentuated by aging [31]

. We are currently addressing this issue by comparing cognitive functioning and brain MRI in aged DM1 and DM2 patients with controls [32] . Our results suggest that the cognitive impairments and MR changes are less marked in the aged DM1 patients (average duration of DM 35 years) , than in DM2 (average known duration of DM 9 years) patients of

similar age (A.M.A. Brands et al. , Utrecht Diabetic Encephalopathy Study Group, unpublished work) . This suggests that, in addition to age, differences in the pathophysiology of DM1 and DM2 are likely to be important determinants of the effects of DM2 on the brain. Direct effects of insulin on the brain? An increasing amount of evidence links insulin

itself to cognitive decline and dementia in DM2 [33 35] . First, alterations in cerebral insulin receptor signalling may be involved, as a cerebral equivalent of peripheral insulin resistance. Secondly, insulin may affect the metabolism of A (amyloid) and tau, two proteins that represent the building C 2005 Biochemical Society

Proteins in Disease 1043 blocks of amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of Alzheimer s disease. Insulin is not a major regulator of glucose use in the brain, in contrast with its prominent action in peripheral tissues such as liver, muscle and fat [36] . Still, insulin and its receptor are widely distributed throughout the brain, with

particular abundance in defined areas, such as the hypothalamus and the hippocampus [37] , and play a role in the regulation of food intake and body weight [36] . In addition, insulin appears to act as a neuromodulator . It influences the release and reuptake of neurotransmitters, and also appears to improve learning and memory [37] . The initial components of

the insulin receptor signalling cascade in the brain are largely similar to those of the periphery [37,38] , but the downstream targets of the cascade are quite different, probably involving, among others, neuronal glutamate receptors [37] . Disturbances in cerebral insulin signalling pathways may be involved in Alzheimer s disease and brain aging [33 35] . Aging is associated with reductions

in the level of insulin and the number of its receptors in the brain [39] . In Alzheimer s disease this age-related reduction in cerebral insulin levels appears to be accompanied by disturbances of theinsulinreceptorsignalling[39],leadingtothequalification ofAlzheimer sdiseaseas aninsulin-resistantbrainstate [40] . The relation between insulin and the metabolism of A and tau is also receiving increasing attention [33,35] . A is derived from the

so-called amyloid precursor protein. After secretion into the extracellular space A can aggregate with otherproteins,toformsenileplaques.Alternatively,excessive A can be cleared through LDL-receptor-related protein mediated endocytosis, or through direct extracellular proteolyticdegradation[41].ThislatterprocessinvolvesIDE (insulin-degrading enzyme) [42] . Insulin appears to stimulate A secretion,andinhibitstheextracellulardegradationofA by competition from IDE [33] . A recent histopathological study of the hippocampus in patients with Alzheimer s disease reported marked reductions in

IDE expression, and IDE mRNA levels, relative to controls [43] . Interestingly, this reduced expression only occurred in patients with the APOE (apolipoprotein E) e4 allele. An interaction with the APOE e4 genotype has also been demonstrated for the risk of Alzheimer s disease in DM patients [8] , an observation that was supported by neuropathological results [8] . Although

the concepts of cerebral insulin resistance , and insulin-induced amyloid pathology are an attractive explanation for some of the effects of DM2 on the brain, there are still many loose ends. In contrast with the increasing body of knowledge on the mechanisms of insulin resistance in peripheral tissues [44] , we know relatively little on how DM2 and its treatment

affect cerebral insulin and its receptor. Moreover, the knowledge on the role of insulin in brain physiology is far from complete. For example, in apparent contrast with previous observations that hippocampal insulin receptor expression and signalling in rats are up-regulated following a spatial learning task in a water maze [45] , mice with a targeted knockout of insulin receptors in the brain readily

learn this same task [46] . Hopefully, ongoing research in this rapidly evolving field of research will clarify these issues. Conclusion Several mechanisms may be involved in accelerated cognitive decline and the increase of dementia in patients with DM2 (Figure 1) . Because these different mechanisms interact at several levels, it is unlikely that future studies will

detect a single factor that link DM to impaired cognition. It may be possible, however, to identify processes, or clusters of risk factors, that explain at least part of the association, and can be targeted by preventive measures. These preventive measures may not only include improvement of glycaemic control [47] , but could also be directed at vascular risk factors andinsulinmetabolism.Infact,thereisalreadysomeevidence

from studies in non-DM patients that these latter approaches may be successful. For example, treatment of vascular risk factors, such as hypertension, may decrease the incidence of dementia in the context of ischaemic cerebrovascular disease [48] . Moreover, a recent exploratory randomized placebocontrolledtrialwiththeinsulin-sensitizingcompoundrosiglitazone showed an amelioration of both cognitive decline and abnormalities in cerebrospinal fluid A in non-DM patientswithearlyAlzheimer sdisease[49].Thechallengefor future studies

will be to determine what preventive strategy should be applied in which DM2 patient, at what stage of the disease. The Utrecht Diabetic Encephalopathy Study Group consists of (in alphabetical order) : Department of Clinical Neurophysiology: A.C. van Huffelen; Department of Internal Medicine: H.W. de Valk; Julius Center for Health Sciences and Primary Care: A. Algra, G.E.H.M. Rutten; Department

of Medical Pharmacology: W.H. Gispen; Department of Neurology: A. Algra, G.J. Biessels, L.J. Kappelle, S.M. Manschot, J. van Gijn; Department of Neuropsychology and Helmholtz Research Institute: A.M.A. Brands, E.H.F. de Haan, R.P.C. Kessels, E. van den Berg; Department of Radiology: J. van der Grond, all part of the University Medical Center, Utrecht, The Netherlands. The research of the Study Group

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